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Endocrinology. 2017 Jun 1;158(6):1951-1963. doi: 10.1210/en.2016-1913.

Vitamin D Receptor-Dependent Signaling Protects Mice From Dextran Sulfate Sodium-Induced Colitis.

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Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47906.
Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47906.
Purdue University Interdisciplinary Life Sciences Ph.D. Training Program, Purdue University, West Lafayette, Indiana 47906.
Center for Cancer Research, West Lafayette, Indiana 47907.


Low vitamin D status potentiates experimental colitis, but the vitamin D-responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CEC-VDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (Mɸ) cytokines tumor necrosis factor-α, nitric oxide synthase 2, and interleukin-1β were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal Mɸs demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated Mɸ phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of Mɸ biology).

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